title: Metastasin S100A4 is a mediator of sex hormone-dependent formation of the cortical bone.
abstract: S100A4 is a Ca-binding protein participating in regulation of cell growth, survival, and motility. Here we studied the role of S100A4 protein in sex hormone-regulated bone formation. Bone mineral density in the trabecular and cortical compartments was evaluated in female S100A4 knockout (KO), in matched wild-type (WT) counterparts, and in WT mice treated with lentiviral small hairpin RNA construct inhibiting the S100A4 gene transcription or with a nontargeting construct, by peripheral quantitative computed tomography. The effect of sex hormones on bone was measured 5 weeks after ovariectomy (OVX) and/or dehydroepiadrosterone treatment. S100A4KO had an excessive trabecular and cortical bone formation compared with the age- and sex-matched WT mice. S100A4KO had an increased periosteal circumference (P = .001), cortical thickness (P = .056), and cortical area (P = .003), which predicted 20% higher bone strength in S100A4KO (P = .013). WT mice treated with small hairpin RNA-S100A4 showed an increase of the cortical bone parameters in a fashion identical with S100A4KO mice, indicating the key role of S100A4 in the changed bone formation. S100A4KO mice had higher serum levels of osteocalcin and a higher number of osteocalcin-positive osteoblasts under the periosteum. OVX-S100A4 resulted in the loss of the cortical bone supported by high CTX-I levels, whereas no such changes were observed in OVX-WT mice. S100A4KO mice resisted the dehydroepiadrosterone -induced bone formation observed in the WT counterparts. Our study indicates that S100A4 is a regulator of bone formation, which inhibits bone excess in the estrogen-sufficient mice and prevents the cortical bone loss in the estrogen-deprived mice.
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Göteborg, S-41346 Göteborg, Sweden. malin.erlandsson@rheuma.gu.se
authors.forename: Malin C
authors.initials: MC
authors.lastname: Erlandsson
authors.forename: Li
authors.initials: L
authors.lastname: Bian
authors.forename: Ing-Marie
authors.initials: IM
authors.lastname: Jonsson
authors.forename: Karin M
authors.initials: KM
authors.lastname: Andersson
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000818:Animals; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D010052:Ovariectomy; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D015675:Osteocalcin; D003687:Dehydroepiandrosterone